Development of Toll-Like Receptor Agonists as Neuroprotectants in Brain Ischemia

描述（由申请人提供）： 缺血预处理耐受的内源性机制已经揭示了大脑重新编程（预处理）其对急性缺血的反应的能力，从诱导细胞损伤信号级联到诱导神经保护途径（耐受）。这种内源性神经保护通过Toll样受体（TLR）信号传导发生，其将对中风的炎性（损伤性）反应重新编程为抗炎（神经保护）反应。我们提供TLR 9和TLR 7的优选激动剂（CpG ODN和咪喹莫特-顶Q）分别作为预防性神经保护对抗中风的先导化合物。虽然已经产生了可靠的啮齿动物数据，但过去和最近的翻译失败需要额外的临床前评价。因此，我们开发了一种新的灵长类动物中风模型，用于评估推定的药物治疗，并建议对我们最近发现的神经保护剂进行严格的试验，以建立基本的疗效和药代动力学数据。因此，我们的初步研究支持新的强大的神经保护策略，用于高风险中风患者，以进一步测试在非人灵长类动物通过：目的1。确定最佳剂量以实现TLR 9（K-和D-混合CpG ODN）和TLR 7（IMQ）候选药物作为皮质卒中的NHP模型中的预防性治疗的神经保护功效。目标2.确定K-和D-混合CpG ODN和IMQ作为皮质卒中的NHP模型中的预防性治疗的神经保护功效的时间窗。目标3。确定CpG ODN（K和D混合物）和IMQ作为预防性治疗在老年NHP皮质卒中模型中的神经保护功效。目标4。确定重复施用CpG ODN（K-和D-混合物）和IMQ作为皮质中风的NHP模型中的预防性治疗的神经保护功效。目标5。确定最佳CpG ODN（K-和D-混合物）和IMQ作为女性NHP皮质卒中模型中预防性治疗的神经保护功效。目标6。确定CpG ODN（K-和D-混合物）和IMQ作为潜在中风治疗剂的药代动力学和毒性特征。目标7。根据疗效、药代动力学和毒性特征，提交最佳TLR候选药物的IND申请。 相关性：许多保护大脑免受中风的药物治疗已经尝试过并失败了。这一提议提供了一种基于大脑自身内源性神经保护程序的新方法。我们将研究3种已被证明对人类安全的新药，并测试它们作为预防缺血性脑损伤的药物。我们将首先在相关的灵长类中风模型中测试这些药物，然后再进行临床试验，以治疗未来中风风险非常高的人类。

DESCRIPTION (provided by applicant): Endogenous mechanisms of ischemic preconditioning-tolerance have reviled the brain's ability to reprogram (precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an anti- inflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod - IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential efficacy and pharmacokinetic data. Thus our preliminary studies support new robust neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy for TLR9 (K- and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for K- and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and D mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K- and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an IND application for the optimal TLR candidate based on efficacy, pharmacokinetics and toxicity profiles. RELEVANCE: Many drug treatments to protect the brain from stroke have been tried and failed. This proposal offers a new approach based on the brain's own endogenous neuroprotective program. We will investigate 3 new drugs that have been shown to be safe in humans and test them as prophylaxis against ischemic brain injury. We will first test these drugs in a relevant primate model of stroke before moving to a clinical trial to treat humans that are at very high risk for future stroke.